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Current Computer-Aided Drug Design

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ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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Research Article

Synthesis, Antitumor Activity, Molecular Docking and DFT Study of Novel Pyrimidiopyrazole Derivatives

Author(s): Asmaa M. Fahim*, Mohamed S. Elshikh and Noura M. Darwish

Volume 16, Issue 4, 2020

Page: [486 - 499] Pages: 14

DOI: 10.2174/1573409915666190710094425

Price: $65

Abstract

Background: In this investigation, 2-cyano-N-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) acetamide (3) reacts with dimethylformamide dimethyl acetal (DMF-DMA) to afford the corresponding (E)- 2-cyano-3-(dimethylamino)-N-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)acrylam-ide (4) utilizing microwave irradiation. The condensation reactions of acrylamide derivative 4 with hydrazine derivatives obtain pyrazole derivatives 6a and 6b; respectively. The synthesized compounds demonstrate in vitro antitumor activity against liver tumor cell line HepG2. Furthermore, additional studies were carried out on the most effective compound 6b to evaluate the potential interaction against 4hdq synthase complex with ΔE= -4.5Kcal/mol and with short distance = 1.727Å and 2.027Å, respectively. The comprehensive theoretical studies of compounds 6a and 6b is based on bond length, bond angles and energy gap HOMO-LUMO. In addition, the vibrational frequencies of optimized compounds 6a and 6b were examined through DFT/B3LYP/6+31G(d) basis set.

Methods: In this research, synthesis of novel pyrimidiopyrazole derivatives calculated the computational studies to find suitable drug-receptor interactions and biological activity.

Results and Discussion: The synthesized pyrimidiopyrazole derivative 6b exhibited high antitumor activity IC50 =12.6 μg/ml and interacted it with 4hdq synthase complex with ΔE=-4.5Kcal/mol and with short distance = 1.727Å and 2.027Å. Furthermore, the optimized compounds utilize Gaussian 09W.

Conclusion: In the optimized pyrimidiopyrazole derivatives, 6b showed better antitumor activity HeG-2 against 5-flurouracil due to its energy and confirmed more potent of hydrogen bond interaction with protein pocket.

Keywords: Enaminonitrile, aminopyrazole, antitumor activity, molecular docking, 4hdq synthase complex, computational study, FT-IR analysis.

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